Pomalidomide for the management of refractory multiple myeloma

Multiple myeloma is a plasma- cell-derived neoplasm char- acterized by bone lesions, hypercalcemia, anemia, and renal insufficiency. In the United States, an estimated 24,050 new cases and 11,090 deaths due to multiple myelo- ma were projected to occur in 2014.1 Overall five-year survival trends have increased from 25% in 1975–77 to 43% in 2002–08 (p < 0.05).1 These improvements may be due to the development of immunomodulat- ing agents such as thalidomide, lenalidomide, and bortezomib or from advancements made in bone marrow transplant options. Multiple myeloma is sensitive to a variety of drugs; however, it is not considered a curable disease, and relapse is com- mon.2 The treatment options for symptomatic multiple myeloma are stratified by whether the patient is a beyond primary treatment, such as maintenance or salvage regimens, depend on patient response to pri- mary treatment and transplanta- tion. There is a need for alternative therapies when patients do not respond to first-line therapies, as the median overall survival and event- free survival times for these patients are low. Pomalidomide is a second- generation immunomodulatory drug thought to have antiproliferative and direct cytotoxic effects.5 It may impact multiple myeloma disease progression by inhibition of osteo- clastogenesis, the process responsible for promoting the growth of osteo- clasts that break down bone tissue.6 Pomalidomide has been approved by the Food and Drug Administra- tion (FDA) for patients with mul- tiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and whose disease has progressed on or within 60 days of completion of the last therapy.5-7 This article reviews the pharmacology, pharmacokinetics, clinical efficacy, safety, dosage and administration, and place in therapy of pomalidomide. Pharmacology Similar to thalidomide and len- alidomide, pomalidomide is an im- munomodulatory agent with activ- ity in relapsed multiple myeloma.7,8 Pomalidomide exerts its effect on hematopoietic tumor cells by in- hibiting proliferation and inducing apoptosis. The antiproliferative effect of pomalidomide extends to multiple myeloma cell lines that are resistant to lenalidomide.7-9 When combined with dexamethasone, pomalidomide induces apoptosis of tumor cells in cell lines both sensitive and resistant to lenalidomide. Pomalidomide enhances the number and function of T cells and natural killer cells and inhibits monocyte produc- tion of proinflammatory cytokines, such as tumor necrosis factor- and interleukin-6.7 While several mechanisms have been suggested to explain the antineoplastic effects of immunomodulatory agents, in- cluding pomalidomide, the precise mechanism remains unclear and is an area for continued research. Pharmacokinetics After the administration of a sin- gle oral dose of pomalidomide, the maximum concentration is achieved after 2–3 hours, with disproportion- ate increases in systemic exposure.7 In patients with multiple myeloma receiving oral pomalidomide 4 mg once daily as monotherapy or in combination with dexamethasone, the area under the concentration curve was 400 ng/hr/mL and the maximum plasma concentration was 75 ng/mL. Accumulation of pomalidomide after multiple doses occurs at rates of 27–31%. Pomalido- mide has a mean volume of distribu- tion of 62–138 L at steady state, and its non-concentration-dependent plasma protein binding ranges from 12% to 44%. Pomalidomide is me- tabolized in the liver via cytochrome P-450 (CYP) isoenzymes 1A2 and 3A4, with minor contributions from CYP2C19 and CYP2D6. Its me- dian half-life in plasma in healthy subjects is approximately 9.5 hours compared with 7.5 hours in patients with multiple myeloma, with a total body clearance of 7–10 L/hr. In a small pharmacokinetic study con- ducted by Hoffman and colleagues,10 eight subjects received a single 2-mg dose of pomalidomide administered orally as a suspension to evaluate the pharmacokinetic profile in healthy men. The investigators concluded that over 70% of the pomalidomide dose was absorbed. They also found a half-life of 9–14 hours, similar to that described in the prescribing information. Clinical efficacy Phase I studies. In an open- label, single-center, Phase I, dose- escalation study, pomalidomide was administered in a “3+3” design to determine the maximum toler- ated dose.11 Three patients with confirmed and measurable multiple myeloma were recruited at a time and assigned to receive 1, 2, 5, or 10 mg of pomalidomide for a minimum of 28 days. The mean age of patients enrolled in this trial was 66 years, and patients received previous treatment with stem cell transplantation or thalidomide and had an Eastern Co- operative Oncology Group (ECOG) score of 0–1. If no dose-limiting tox- icities were observed, the next group of patients was enrolled at the next highest dose. Overall, pomalidomide 2 mg daily was the maximum toler- ated dose, and neutropenia was the dose-limiting toxicity in this study. In a subsequent Phase I trial,pomalidomide was studied in an alternative-day dosing regimen.12 Patients were enrolled in a 3+3 man- ner, similar to the previous study, to receive pomalidomide 1, 2, 5, or 10 mg every other day. However, the methodology was modified later in the study to allow investigators to add dexamethasone 20 mg every other day for days 1–4 and 15–18 to patients who were not responding or were experiencing progressive dis- ease at 12 weeks. The median age of enrolled patients was 58 years (range, 34–75 years), and patients received a median of four prior cycles of che- motherapy (range, one to seven prior cycles). Seventeen patients (85%) had previously received thalidomide, and 13 patients (65%) had previously received high-dose chemotherapy with stem cell transplantation. The addition of dexamethasone occurred in 9 patients (41%). Three patients were advanced from pomalidomide 5 mg every other day to 10 mg every other day, and all 3 developed dose- limiting grade 4 neutropenia and had to discontinue pomalidomide. When dexamethasone was added to the reg- imen of the 9 patients who had dis- ease progression or prolonged non- responsive disease, 2 patients (22%) had a very good partial response, 1 (11%) had a partial response, 1 (11%) had a minimal response, 3 (33%) experienced disease stabiliza- tion, and 2 (22%) had no response. Minimal response was defined as a 25–49% reduction in the quantita- tive serum immunoglobulin or the urinary M component. Additional response criteria from the Interna- tional Myeloma Working Group are provided in the appendix. Phase II studies. The first Phase II trial of pomalidomide was conduct- ed to establish the drug’s maximum tolerated dose when used in combi- nation with dexamethasone.13 The trial also evaluated a second group of patients to determine whether increasing the dose from 2 to 4 mg had any effect on disease response. Pomalidomide 2 mg daily was given with weekly doses of dexametha- sone 40 mg for a 28-day cycle. The intent-to-treat population included 60 patients (37 in the first group, 23 in the second group). Overall, a confirmed response was achieved in 38 patients (63%) (95% confidence interval [CI], 50–75%). Complete re- sponses, very good partial responses, and partial responses were observed in 5%, 28%, and 30% of participants, respectively. Another Phase II trial focused on patients with disease refractory to treatment with lenalidomide, de- fined as disease progression on or within 60 days after discontinuation of lenalidomide.14 Pomalidomide and dexamethasone were given to- gether, with pomalidomide 2 mg given continuously on days 1–28 of a 28-day cycle and dexamethasone 40 mg administered weekly. The dose of pomalidomide was not increased. A total of 34 patients were recruited, and all were evaluable. Patients had a median age of 62 years, and 68% had undergone previous autologous stem cell transplantation. All patients had previous treatment with lenalido- mide, and a majority of patients had previously received thalidomide and bortezomib (58% and 59%, respectively). Confirmed response, defined as progressive response or greater at two consecutive assess- ments, was achieved in 32% of the patients enrolled in the study (95% CI, 19–53%). Mean progression-free survival (PFS) was 4.8 months (95% CI, 2.7–10.1 months). The results of this study suggested that cross- resistance does not occur between lenalidomide and pomalidomide, providing another treatment option for patients with refractory multiple myeloma. To further evaluate the activity of pomalidomide in patients with refractory disease, another Phase II trial was conducted to evaluate pa- tients with dual-refractory disease, meaning that the multiple myeloma was refractory to both bortezomib and lenalidomide.15 The primary ob- jective of the study was to determine the safety of administering pomalid- omide 4 mg daily, since previous studies had initiated pomalidomide at a dosage of 2 mg daily and either continuously administered 2 mg or increased the dosage to achieve a response. Patients received either pomalidomide 2 or 4 mg daily for 28 days (n = 35 in each group). Pomalidomide and dexamethasone were given together, with pomalido- mide given on days 1–28 of a 28-day cycle and dexamethasone 40 mg administered weekly. Patients had a median age of 62 years (range, 39–77 years), and a majority had an ECOG performance status of 0–1. The con- firmed response rate was 26% (95% CI, 12–43%) in the 2-mg group versus 28% (95% CI, 14–46%) in the 4-mg group. PFS was longer in the 2-mg group (6.5 months [95% CI, 3.9–8.9 months]) than in the 4-mg group (3.2 months [95% CI, 1.9–8.6 months]). Overall, there was no ben- efit in starting patients at a 4-mg dose due to similar findings in PFS, based on confidence intervals. Optimum dosing of pomalido- mide with low-dose weekly dexa- methasone was addressed in another Phase II evaluation.16 A total of 84 patients were recruited and ran- domized to receive either pomalido- mide 4 mg daily on days 1–21 of a 28-day cycle (n = 43) or pomalido- mide 4 mg daily for a continuous 28-day cycle (n = 41). Both groups received weekly doses of dexametha- sone 40 mg. Of note, 38% of the patients enrolled in this study had cytogenetic abnormalities indicative of a poor prognosis, either deletion 17p or translocation t (4;14) on bone marrow plasma cells. Patients had a median age of 60 years (range, 42–83 years), 81% had received au- tologous stem cell transplantation, and 76% had disease refractory to both bortezomib and lenalidomide. The overall median duration of re- sponse was 7 months, with 44% of patients responding at 12 months (hazard ratio [HR], 0.91; 95% CI, 0.4–2.0; p = 0.817). Median over-all survival was similar between groups (14.9 months [9 months to undetermined] in the 21-day group versus 14.8 months [9–20 months] in the continuous 28-day group (HR, 1.23; 95% CI, 0.7–2.0; p = 0.45). The study was not powered to detect a difference between the two regimens; however, after ob- serving similar response rates and survival times, the 21-day regimen was favored as it minimized toxic- ity and allowed for the cessation of treatment from unnecessary doses of pomalidomide. Both bortezomib and lenalido- mide have been administered with an alkylating agent to enhance response rates and prolong disease-free intervals. Therefore, a Phase I/II study was performed to evaluate the addition of cyclophosphamide to a regimen of pomalidomide and prednisone in patients with refractory multiple myeloma.17 Overall, 69 patients were enrolled in the study. Patients had a median age of 69 years (range, 41–84 years) and had received lenalidomide, bortezomib, thalidomide, or an au- tologous or allogeneic stem cell trans- plant as previous treatment. A total of 23 patients had disease relapse, 46 had lenalidomide-refractory disease, and 22 had dual-refractory disease (lenalidomide and bortezomib). Twenty-four patients were enrolled in the Phase I portion and received pomalidomide in dosages ranging from 1 to 2.5 mg daily, cyclophos- phamide 50 mg every other day, and prednisone 50 mg every other day on days 1–28 of a 28-day cycle for six cycles. The Phase I portion of the study found that the maximum tolerated dosage was 2.5 mg daily, which was utilized in the Phase II portion of the study. Twelve patients from the Phase I portion contin- ued on and 45 more patients were enrolled into the Phase II portion. A total of 55 patients were enrolled and evaluated in the Phase II por- tion, in which 55% achieved at least a partial response, and the 1-year PFS was 48% (95% CI, 33–62%) with a median PFS of 10.4 months (95% CI, 7.9–15.8 months). The find- ings of this study are promising for the combination of pomalidomide, cyclophosphamide, and prednisone in patients with refractory multiple myeloma. Further studies are needed to compare this dosing regimen to the regimen of pomalidomide with weekly dexamethasone. Phase III studies. To date, one Phase III trial evaluating the role of pomalidomide for refractory mul- tiple myeloma has been conduct- ed.18 This randomized, multicenter, open-label trial compared pomalid- omide 4 mg daily for 21 days of a 28-day cycle administered with either low-dose dexamethasone 40 mg weekly (n = 153) or high-dose dexamethasone 40 mg on days 1–4, 9–12, and 17–20 (n = 302). A total of 455 patients were enrolled. These patients were elderly (median age, 65 years; range, 35–87 years), had ECOG scores of 0–1, and received a wide range of previous treat- ments, including autologous stem cell transplantation. However, to be included in the study, patients only had to have documented refrac- tory disease to either lenalidomide or bortezomib and have received adequate alkylator treatment as part of a treatment or transplanta- tion regimen. A Kaplan-Meier PFS intention-to-treat analysis revealed that pomalidomide with low-dose dexamethasone had a 4-month PFS (95% CI, 3.6–4.7 months) com- pared with 1.9 months (95% CI, 1.9–2.2 months) with the high-dose dexamethasone (HR, 0.45; 95% CI, 0.39–0.60; p < 0.0001). These findings suggest that pomalidomide with low-dose dexamethasone increases the length of PFS and is associated with increased survival in patients with refractory multiple myeloma who have not responded to either bortezomib or lenalidomide. Safety The most common nonhema- tologic toxicities reported with pomalidomide and low-dose dexa- methasone treatment in Phase II trials were deep vein thrombo- sis (0–9%), fatigue (9–91%), and pneumonia (3–31%).13-17 Patients enrolled in these trials received thromboprophylaxis in the form of aspirin 325 mg, or they could receive low-molecular-weight heparin at the discretion of the physician. The most common hematologic toxicity reported was grade 3/4 neutropenia, which often required discontinua- tion of pomalidomide until neutro- phil counts improved, with a fre- quency of 29–66%.5,13-17 Finally, the frequency of peripheral neuropathy ranged from 26% to 40% and was not a dose-limiting factor. Pomalidomide requires prescrib- ers, patients, and pharmacies to enroll in a risk evaluation and miti- gation strategy (REMS) program due to the drug’s teratogenic risks derived from thalidomide data.7,19,20 These teratogenic effects result in fetal de- formities, behavioral disturbances, and death.7,19 Female patients must adhere to using two forms of birth control four weeks before beginning pomalidomide therapy and four weeks after completing treatment with pomalidomide to ensure that pregnancy does not occur and expose a fetus to pomalidomide.7,19,20 Male patients, including those who have had a vasectomy, must also enroll in the REMS program and use latex or synthetic condoms for up to 28 days after pomalidomide treatment due to pomalidomide’s ability to be excreted into sperm.7 Dosage and administration Pomalidomide is an oral agent available in 1-, 2-, 3-, and 4-mg cap- sules.7 Since the availability and use of pomalidomide are regulated by its manufacturer and FDA through a REMS program, prescribers and dispensing pharmacies undergo spe- cial certification, and patients must provide documentation of safe-use conditions regarding pregnancy, as specified.20 The FDA-approved dosage of pomalidomide is 4 mg orally daily on days 1–21 of repeated 28-day cycles until disease progression is observed.7 Pomalidomide can be administered with or without dexa- methasone for patients who cannot tolerate corticosteroids.Hematologic toxicities necessitate dosage adjustments of pomalido- mide. Treatment should be inter- rupted in the presence of the fol- lowing: an absolute neutrophil cell (ANC) count of <500 cells/L, febrile neutropenia, or a platelet count of <25,000 cells/L; treatment can be resumed at lower doses after resolution of these symptoms. Simi- lar stopping and restarting strategies are recommended by the manufac- turer if other grade 3 or 4 toxicities are experienced.7 Once therapy has been interrupted for the presence of hematologic toxicities, the manufac- turer recommends that therapy not be restarted until the ANC exceeds 500 cells/L and the platelet count exceeds 50,000 cells/L. Place in therapy and future directions Pomalidomide is currently ap- proved for the treatment of refracto- ry multiple myeloma with or without low-dose dexamethasone in patients who have received at least two prior therapies and experienced disease progression on or within 60 days of discontinuation of bortezomib or lenalidomide. Pomalidomide mono- therapy is an option for patients who cannot tolerate corticosteroids.2 The wholesale acquisition cost (WAC) of pomalidomide is $512.32 for each 4-mg capsule.21 Given the recom- mended treatment regimen of one 4-mg capsule once daily for days 1–21 of the 28-day cycle, the total WAC for pomalidomide per treatment cycle is $10,758.72. Pomalidomide is recommended by the National Compre- hensive Cancer Network (NCCN) as salvage treatment for patients who have not responded to other thera- pies for multiple myeloma.2 A com- plete list of other multiple myeloma treatments recommended by NCCN is shown in Table 1. A potential treatment regimen previously discussed for pomalido- mide is its combination with cy- clophosphamide and prednisone.16 A Phase III trial comparing bor- tezomib, pomalidomide, and dexa- methasone with bortezomib and dexamethasone alone is currently underway (OPTIMISMM trial).22 In addition, a Phase I/II trial evaluating the safety and efficacy of pomalido- mide, liposomal doxorubicin, and dexamethasone is currently recruit- ing participants.23 Conclusion Pomalidomide when adminis- tered with weekly low-dose dexa- methasone appears to be both safe and effective for the treatment of relapsed or refractory multiple my- eloma in patients who have had disease progression after completing treatment with bortezomib, lenalido- mide, or both.